The cellular mechanisms by which insulin promotes glucose uptake and metabolism in healthy subjects will be examined utilizing: (a) insulin/hyperglycemic clamp; (b) indirect calorimetry; (c) forearm catheterization; (d) several novel isotopic methodologies recently developed in our laboratory; (e) muscle biopsy. These techniques will allow in vivo quantitation in man of the following parameters: glucose transport and phosphorylation, glucose oxidation, glycolysis, glycogen synthesis, muscle enzyme activity (glycogen synthase and pyruvate dehydrogenase), and hepatic glucose production. Similar measurements will be performed in diabetic and obese patients t delineate the specific intracellular disturbances which are responsible for the insulin resistance (both peripheral and hepatic) in these two common clinical disorders. The contribution of hyperglycemia per se ("glucose toxicity") t the observed defects in insulin action and insulin secretion in non-insulin dependent diabetes mellitus will be explored in detail. We also shall examine the effects of chronic hyperinsulinemia on the oxidative and non-oxidative pathways of glucose disposal.